Heart failure is a pathophysiological state in which the heart is unable to pump sufficient blood to meet the nutrition and oxygen requirement of metabolizing tissues or cells. It is a major complication in many heart diseases. Adults over the age of 40 have an estimated 21% lifetime risk of developing heart failure (Lloyd-Jones et al., 2002, Circulation 106, 3068-72), a condition responsible for more hospitalizations than all forms of cancer combined (American Heart Association. Heart Disease and Stroke Statistics 2003 Update).
Research performed over the last several years demonstrated that transcriptional control and cardiac gene expression seems to play an important role in the pathogenesis and clinical manifestations of heart failure (HF) (Li et al., 2011, Cardiovasc Res. (6):498-512).
Specifically, previous studies demonstrated down-regulation of messenger RNA (mRNA) in HF patients suggesting the importance of molecular mechanisms that suppress mRNA steady state levels (Kaab et al., 2004, J Mol. Med. 82: 308-316).
In recent years, microRNAs (miRNAs, miRs) have emerged as an important novel class of regulatory RNA, which have a profound impact on a wide array of biological processes.
These small (typically 17-24 nucleotides long) non-coding RNA molecules can modulate protein expression patterns by promoting RNA degradation, inhibiting mRNA translation, and also affecting gene transcription. miRs play pivotal roles in diverse processes such as development and differentiation, control of cell proliferation, stress response and metabolism. The expression of many miRs was found to be altered in numerous types of human cancer, and in some cases strong evidence has been put forward in support of the conjecture that such alterations may play a causative role in tumor progression. There are currently about 1223 known human miRs.
Recent data indicates that miRs are also associated with cardiac disease, HF included, and were even more sensitive than mRNAs to the acute functional status of end-stage heart failure (Thum et al., 2007, Circulation. 116: 258-267; Matkovich et al., 2009, Circulation. 119(9):1263-1271).
Current treatments for heart failure include pharmacological methods, devices such as the ventricular assist device (VAD), cardiac resynchronization therapy (CRT), implantable cardioverter-defibrillator (ICD) which is a small battery-powered and heart transplantation. Pharmacological approaches include but are not limited to the use of inotropic agents (i.e., compounds that increase cardiac contractility), neurohumoral blockers (e.g., beta-blockers, angiotensin converting enzyme inhibitors), aldosterone antagonists, diuretics, and vasodilators. However, none of these agents is fully effective either alone or in combination. Availability of transplants is highly limited, and since many individuals suffering from heart failure are in poor health, they are frequently not good surgical candidates. For these reasons, heart failure remains a major cause of morbidity and mortality, particularly in the developed world. In addition, it can be difficult to determine the precise etiology of heart failure, a factor impeding the development of more specific therapies. There is a general lack of diagnostic techniques at the molecular level. Thus, there is a need in the art for the discovery of circulating diagnostic markers which more accurately reflect the genetic predisposition of a subject of developing HF.